2. Academic Validation
  3. Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes

Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes

  • Nucleic Acids Res. 2014;42(16):10245-64. doi: 10.1093/nar/gku757.
Joanna Kowalska 1,  Anna Wypijewska del Nogal 1,  Zbigniew M Darzynkiewicz 1,  Janina Buck 2,  Corina Nicola 2,  Andreas N Kuhn 3,  Maciej Lukaszewicz 1,  Joanna Zuberek 1,  Malwina Strenkowska 1,  Marcin Ziemniak 1,  Maciej Maciejczyk 4,  Elzbieta Bojarska 5,  Robert E Rhoads 6,  Edward Darzynkiewicz 7,  Ugur Sahin 3,  Jacek Jemielity 8
Affiliations

Affiliations

  • 1 Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
  • 2 BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
  • 3 BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany TRON-Translational Oncology at the University Medical Center Mainz, Germany.
  • 4 University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
  • 5 Centre of New Technologies, University of Warsaw, Poland.
  • 6 Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA.
  • 7 Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland Centre of New Technologies, University of Warsaw, Poland.
  • 8 Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland Centre of New Technologies, University of Warsaw, Poland [email protected].
PMID: 25150148 DOI: 10.1093/nar/gku757
Abstract

Modified mRNA Cap Analogs aid in the study of mRNA-related processes and may enable creation of novel therapeutic interventions. We report the synthesis and properties of 11 dinucleotide Cap Analogs bearing a single boranophosphate modification at either the α-, β- or γ-position of the 5',5'-triphosphate chain. The compounds can potentially serve either as inhibitors of translation in Cancer cells or reagents for increasing expression of therapeutic proteins in vivo from exogenous mRNAs. The BH3-analogs were tested as substrates and binding partners for two major cytoplasmic cap-binding proteins, DcpS, a decapping pyrophosphatase, and eIF4E, a translation initiation factor. The susceptibility to DcpS was different between BH3-analogs and the corresponding analogs containing S instead of BH3 (S-analogs). Depending on its placement, the boranophosphate group weakened the interaction with DcpS but stabilized the interaction with eIF4E. The first of the properties makes the BH3-analogs more stable and the second, more potent as inhibitors of protein biosynthesis. Protein expression in dendritic cells was 2.2- and 1.7-fold higher for mRNAs capped with m2 (7,2'-O)GppBH3pG D1 and m2 (7,2'-O)GppBH3pG D2, respectively, than for in vitro transcribed mRNA capped with m2 (7,3'-O)GpppG. Higher expression of Cancer antigens would make mRNAs containing m2 (7,2'-O)GppBH3pG D1 and m2 (7,2'-O)GppBH3pG D2 favorable for Anticancer immunization.

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